An RNA-centric atlas of human cell cycle regulation

Abstract

Cell cycle progression is orchestrated by protein networks coordinating cell growth and division, yet the role of RNA-mediated mechanisms remains underexplored. Here, we define an RNA-centric landscape of human cell cycle control using palbociclib-synchronised normal diploid cells, profiling long non-coding RNAs (lncRNAs), transposable elements (TEs), alternative splicing (AS), and RNA-binding proteins (RBPs). We identify 104 cell cycle-regulated lncRNAs and validate lncRNA ENSG00000230615, whose perturbation alters cell cycle progression and downregulates neighbouring KLF17. Across the transcriptome, 297 TE loci exhibit differential expression dynamics during the cell cycle, with Alu elements upregulated during the G1-to-S transition. Cell-cycle-dependent AS changes affect 598 genes, with alternative 5' splice sites showing the largest shift in usage at the G1-to-S transition. Furthermore, we show that cytokinesis proteins act as non-canonical RBPs with RNA-dependent stability. This study provides a comprehensive resource on RNA-based cell cycle control and highlights an underappreciated layer of regulation mediated by RNA mechanisms.